2abe
From Proteopedia
|
Carbonic anhydrase activators: X-ray crystal structure of the adduct of human isozyme II with L-histidine as a platform for the design of stronger activators
Contents |
Overview
Activation of the carbonic anhydrase (CA, EC 4.2.1.1) isoforms hCA I, II, and IV with l-histidine and some of its derivatives has been investigated, by kinetic and X-ray crystallographic methods. l-His was a potent, activator of isozymes I and IV (activation constants in the range of, 4-33microM), and a moderate hCA II activator (activation constant of, 113microM). Both carboxy- as well as amino-substituted l-His derivatives, such as the methyl ester or the dipeptide carnosine (beta-Ala-His), acted, as more efficient activators as compared to l-His. The X-ray, crystallographic structure of the hCA II-l-His adduct showed the activator, to be anchored at the entrance of the active site cavity, participating in, an extended network of hydrogen bonds with the amino acid residues His64, Asn67, and Gln92 and, with three water molecules connecting it to the, zinc-bound water. Although the binding site of l-His is similar to that of, histamine, the first CA activator for which the X-ray crystal structure, has been reported in complex with hCA II (Briganti, F.; Mangani, S.;, Orioli, P.; Scozzafava, A.; Vernaglione, G.; Supuran, C. T., Biochemistry1997, 36, 10384) there are important differences of binding, between the two structurally related activators, since histamine interacts, among others with Asn67 and Gln92 (similarly to l-His), but also with, Asn62 and not His64, whereas the number of water molecules connecting them, to the zinc-bound water is different (two for histamine, three for l-His)., Furthermore, the imidazole moieties of the two activators adopt different, conformations when bound to the enzyme active site. Since neither the, amino- nor carboxy moieties of l-His participate in interactions with, amino acid moieties of the active site, they can be derivatized for, obtaining more potent activators, with pharmacological applications for, the enhancement of synaptic efficacy. This may constitute a novel approach, for the treatment of Alzheimer's disease, aging, and other conditions in, need of achieving spatial learning and memory therapy.
Disease
Known disease associated with this structure: Osteopetrosis, autosomal recessive 3, with renal tubular acidosis OMIM:[611492]
About this Structure
2ABE is a Single protein structure of sequence from Homo sapiens with ZN, HG and HIS as ligands. Active as Carbonate dehydratase, with EC number 4.2.1.1 Full crystallographic information is available from OCA.
Reference
Carbonic anhydrase activators: X-ray crystal structure of the adduct of human isozyme II with L-histidine as a platform for the design of stronger activators., Temperini C, Scozzafava A, Puccetti L, Supuran CT, Bioorg Med Chem Lett. 2005 Dec 1;15(23):5136-41. Epub 2005 Oct 7. PMID:16214338
Page seeded by OCA on Mon Nov 12 20:48:25 2007
